No door? No problem. T. cruzi uses the window to cause Chagas Disease

For invasive pathogens the only way to survive, and consequently make you sick, is to get inside your cells. This is a rough exercise as you have an immune system working everywhere in the body to prevent this and the cell to be invaded is none too happy with the idea either so invasive pathogens must use tricks.

After evading or surviving the immune system, another post for another day, some exploit a mechanism called receptor mediated endocytosis (RME), in which the pathogen binds to a receptor on the cell triggering the cell to alter its shape to internalise the pathogen. RME is used by cells to recycle extracellular components but it a pathogen can make itself fit the receptor instead it can trick the cell into giving it free access to its insides.

Another mechanism, commonly employed by membrane bound viruses, is membrane fusion. Given that membrane bound viruses contain a secondary structure called the nucleocapsid, which houses the genome, they can fuse their own membranes with the host cell which results in the nucleocapsid's release into the cytoplasm.

Chagas Disease is named after the super moustachioed Dr. Carlos Chagas, physician, bacteriologist, parasitologist, epidemiologist and infectious disease superstar. Chagas’ story is interesting enough for its own post, but in short his work achieved a great many things and he is best known for being the only person in history to, on his own, describe a pathogen, its vector, the effect on experimental hosts, clinical manifestations in humans and its epidemiology! All this work would, and should, have been enough for a Nobel Prize, which he was twice nominated for in 1913 and 1921, but Chagas was blocked by his arch nemesis the also impeccably moustachioed Dr. Júlio Afrânio Peixoto a prominent eugenicist.

Chagas’ discovery showed that triatome bugs like Rhodnius prolixus spread the parasite between people by biting infected individuals and then moving to new food sources. Chagas thought the parasite was spread as a result of the bite but later studies showed that the parasite survived the insect’s digestive tract and entered the new host when they scratched at the bite pushed the insect’s faeces into the wound. From there the parasite invades nearby cells and reverts to its reproductive form, replicates and then releases the invasive form of the parasite back into the blood to repeat the cycle.

The disease itself is spread into 2 distinct stages. The initial acute stage results in flu-like symptoms (which I have decided would be a great name for a blog given that everything has flu-like symptoms) and a raised area at the bite site. Experienced physicians can also spot something called ‘Romaña's sign’ which is a swelling of the eyelids on the side of the face that was bitten. Most people survive the acute stage with no problems but few actually cure themselves of the disease. The second stage of disease depends on how the host responds to the chronic infection.

Indeterminate Chagas disease is the good version. These people respond positively to Chagas tests but are asymptomatic. The bad version, determinate Chagas disease, is experienced by 20% - 40% of people who pick up the parasite.

Those that pick up the symptomatic chronic form of Chagas disease suffer a number of problems centered around parts of the body that get a lot of blood a lot of the time like the heart, brain and gut.

The parasites activity at the gut paralyses it, resulting in permanent dilation of the gut. This becomes an enormous problem as the co-ordinated contraction of the gut (peristalsis) is what keeps food material moving. If it doesn’t move it rots which is never good but can also result in the consolidation of faecal matter and the formation of faecal tumours, which are even less good.

If the brain and central nervous system are involved then dementia and confusion can set in as well as destruction of motor or sensory neurons effectively paralysing or numbing the sufferer.

Most deaths associated with Chagas disease are due to destruction of cardiac tissues leading to enlargement of the heart, loss of rhythm and subsequent decrease in the efficiency of the heart, clinically referred to as dilated cardiomyopathy. This often results in sudden death as the heart fails and stops.

What makes all of this even more saddening is that currently there is no vaccine and treatment options are limited but the recent observation of T. cruzi’s novel invasion mechanism might enable the development of novel drugs to prevent the continuous re-infection.

T. cruzi invades cells by inducing cell membrane damage. The cell’s response to membrane damage is allows calcium to flow into the cell, which triggers a number of cellular activities including the fusion of lysosomes with the cell membrane. Cells are highly compartmentalised and each component has a specific activity. In a way you can think of a cell as a house where each room has its own activity, bedrooms are for sleeping, kitchens for cooking etc. Lysosomes are like the garbage disposals of cells that contain all the degradative enzymes for the breakdown of cellular waste among other jobs (thanks Dr. Simon :D).

The release of the lysosomal contents results in some of these degradative enzymes getting into the damaged sections of membrane and breaking it further allowing its internalisation and destruction by the cell.

So rather than binding a receptor to force internalisation the parasite damages the cell membrane triggering a repair mechanism that drags the parasite into the cell alongside the membrane to be destroyed.

The really important observation here is that the damage caused by the parasite is due to its binding of the membrane intimately and then trying to swim away causing mechanical stress on the membrane resulting in damage. This suggests the possibility of drug development targeted at preventing attachment of T. cruzi, which would limit the internal spread of the parasite and might even allow immune system clearance and cure of the disease!

3 comments:

Umm... I'm guessing that Chagas' disease occurs in certain areas of the world, rather than it lurking everywhere to jump into insect bites?? As the effects sound rather devastating, please reassure the hypochondriacs they are unlikely to catch it in downtown Adelaide or New York! Or is it like an invasion of the zombies?

Not limited to certain parts of the world. The kissing bug can be found all over North America. Up until recently the percentage of bugs carrying the T Cruzi parasite was small but recently it has been growing. Possibly due to mass immigration from Mexico and South America. Blood banks recently began testing for Chagas and were surprised by the number of people carrying the disease in southern California.